This proposal is in response to the request for application, RFA-12-013, Genomic Research in AAT-Deficiency and Sarcoidosis study (GRADS). As a center with significant expertise in sarcoidosis and alpha- 1 anti-trypsin deficiency (AATD) from a clinical and research standpoint, we have the ability to recruit patients and controls for this RFA as well as obtain accurate phenotyping and to collect relevant specimens for us in a center-wide study. Our investigators have expertise in the scientific focus of the RFA, including genomics, immunology/immunophenotyping, and clinically based research, which would serve as a resource for this U01 grant. The goal of this study is to define the molecular and immunologic phenotype or signature of sarcoidosis and AATD, two diseases that result from genetic and environmental interaction. Based on this information we propose three aims to address our hypothesis that key immune genes and pathways result in differential immune response and immune modulation in both sarcoidosis and AATD and ultimately modify disease phenotype and severity. The first aim is proposed as a study-wide proposal, to be conducted at all sites, to define the host innate and immune molecular profile in sarcoidosis and AATD bronchoalveolar lavage cells and peripheral blood cells compared to normal healthy controls and smoking-induced COPD controls. Genome-wide transcription profiles would be used to define the molecular profiles, in cases-compared to controls, but also in a case-comparison study to define the genes associated with disease and more severe forms of disease. Evaluation of BAL microbiome is proposed to further define the molecular profiles of disease and disease phenotype, as it is likely that microbiologic etiology of disease determines disease phenotype in sarcoidosis, while the microbiome modifies disease phenotype in AATD. Aims 2 and 3 will serve as our clinical site-specific protocol, but will provide synergy and integration with the study-wid research. In Aim 2, we will determine if there is a deficient or dysfunctional immune regulation occurring in the lung of sarcoidosis and AATD, focusing on T-regulatory cells and Th1/Th17 phenotype, in disease compared to controls and in more severe disease. This information will provide important mechanistic data, but also be evaluable for use by the study-wide protocols as immunophentoyping information. Finally, in Aim 3, we will integrate information from Aims 1 and 2 and from prior genetic studies to date to define genetic determinants and expression quantitative loci that determine the immunogenomic response in disease and modify disease severity. This information will not only provide a resource to the U01 study-wide information, but information that may have implications in disease diagnosis and prognois and provide targets for therapies for future study. RELEVANCE: Sarcoidosis and AATD are rare diseases that result in significant morbidity and mortality. The reason why some develop these diseases and others do not and the natural history is not well understood. This proposal will define factors that may serve as biomarkers or predictors of disease and ultimately even need for therapy. The data derived will define pathogenetic mechanisms of disease and severe disease. Finally, the data and information for the GRADS U01 that will be available in the public domain to be used by other investigators for future study of disease mechanisms and susceptibility.